[心血管钙通道多样性的分子层面]

CRBM-CNRS UPR 9008, INSERM U 249, Montpellier.

C R Seances Soc Biol Fil. 1996;190(2-3):219-35.

Voltage-dependent calcium channels control various physiological functions such as the excitation-contraction coupling, the secretion of hormones or the release of neurotransmitters in the nervous system. Molecular genetics has allowed to provide a structural basis to the functional diversity of calcium channels and to initiate studies to understand the relations between the structure and the function of these excitable proteins. The aim of our research is to compare both the functional and structural properties of calcium channels from various tissues. The studies on dissociated or cultured cells allow to describe their properties, regulation, pharmacology and pathophysiology in native tissues. Structure-functions studies using reconstitution models such as Xenopus oocytes aim to understand the molecular basis underlying their diversity. Calcium channels are composed of several subunits (alpha 1, alpha 2-delta, beta, gamma). Six genes have been identified as coding for the pore subunit (alpha 1) which determines the general profile and in particular the pharmacology of a given calcium channel. However, the auxilliary subunits and mainly beta subunits for which 4 genes and several variants have been isolated, are able to modify the level of expression and the properties of a calcium current directed by an alpha 1 subunit in a reconstitution model. The structure-function studies are now mainly designed to investigate the functional consequences of the interaction alpha 1-beta on the electrophysiological and pharmacological properties. These studies should lead to a better understanding of the molecular basis underlying the diversity between cardiac and vascular calcium channels and also of their respective implication in pathophysiology. The co-expression of several families of calcium channels in a single neuron do not allow properly to investigate the properties and the regulation (by phosphorylation or G proteins) of the neuronal calcium channels which are involved in neurosecretion. The use of reconstitution models will provide a better characterization of neuronal calcium channels and should help to the development of new drugs of therapeutical interest.

电压依赖性钙通道控制着各种生理功能，如兴奋 - 收缩偶联、激素分泌或神经系统中神经递质的释放。分子遗传学已为钙通道的功能多样性提供了结构基础，并开启了旨在理解这些可兴奋蛋白结构与功能之间关系的研究。我们研究的目的是比较来自不同组织的钙通道的功能和结构特性。对解离或培养细胞的研究有助于描述其在天然组织中的特性、调节、药理学和病理生理学。使用非洲爪蟾卵母细胞等重组模型进行的结构 - 功能研究旨在了解其多样性背后的分子基础。钙通道由几个亚基组成（α1、α2 - δ、β、γ）。已鉴定出六个基因编码孔道亚基（α1），该亚基决定了特定钙通道的总体特征，特别是药理学特性。然而，辅助亚基，主要是已分离出4个基因和多个变体的β亚基，能够在重组模型中改变由α1亚基引导的钙电流的表达水平和特性。现在结构 - 功能研究主要旨在研究α1 - β相互作用对电生理和药理学特性的功能影响。这些研究应有助于更好地理解心脏和血管钙通道之间多样性的分子基础，以及它们在病理生理学中的各自作用。单个神经元中几种钙通道家族的共表达无法恰当地研究参与神经分泌的神经元钙通道的特性和调节（通过磷酸化或G蛋白）。重组模型的使用将更好地表征神经元钙通道，并应有助于开发具有治疗意义的新药。